This proposal is designed to characterize at the DNA level the mutations which produce hemoglobin H disease during the evolution of leukemia, which arise in mentally retarded individuals with hemoglobin H disease in the United States, and which occur in Israeli individuals with hemoglobin H disease. This latter study will include identification of the alleles which make up the genotype of these hemoglobin H disease patients, the phenotypic pattern of each allele when it appears in families of patients with hemoglobin H disease as a single defect and the correlation between clinical data and the various alleles for treatment and councilling. All projects are organized into 2 phases: 1) restriction endonuclease mapping using conventional Southern Blots and nick translated 32P labeled cloned genomic probes to characterize the gene map of each abnormal state; 2) molecular cloning of interesting alleles (from the familial Israeli patients), mutations in the mentally retarded, and regions flanking the globin genes in the acquired hemoglobin H disease - pre-leukemic patients when these mutations are identified as different from the corresponding genes in the somatic tissues of these patients. In addition, chromosome 16 specific gene libraries from the pre-leukemic patients will be constructed for use in the identification of new sequences or rearrangements not present in the genome of normal individuals which appear during the evolution of the leukemic state and hemoglobin H disease in these patients. The application of the techniques of recombinant DNA research to each of three biologically unique disorders of alpha globin gene expression are designed to 1) characterize the genetics of familial hemoglobin H disease in a region of the world (Israel) where the information could be used for councilling; 2) to determine if the genetic patterns associated with disordered alpha globin gene expression in developmentally abnormal individuals uncovers a different class of mutations of general significance for differentiation and development; and 3) the study of abnormal alpha globin gene expression in pre-leukemics to identify potential regulatory sites or recombination events which alter globin gene expression.